Imidazolinyl phenyl carbonyl compounds, acid addition salts and related compounds

ABSTRACT

This invention is concerened with tetrahydropyrimidinyl phenyl carbonyl acid addition salts, imidazolinyl phenyl carbonyl acid addition salts, dihydroimidazoisoindolols, tetrahydropyrimidoisoindolols, and tetrahydropyrimidoisoindolol acid addition salts which are all pharmacologically efficacious as anti-depressants. The tetrahydropyrimidinyl phenyl carbonyl acid addition salts, the tetrahydropyrimidoisoindolols and the tetrahydropyrimidoisoindolol acid addition salts are also efficacious as diuretics while the imidazolinyl phenyl carbonyl acid addition salts and the dihydroimidazoisoindolols are effficacious as anorexiants. This invention is also concerned with several processes for the preparation of these compounds.

United States Patent 191 Sulkowski Feb. 18, 1975 IMIDAZOLINYL PHENYL CARBONYL COMPOUNDS, ACID ADDITION SALTS AND RELATED COMPOUNDS [75] Inventor: Theodore S. Sulkowski, Wayne, Pa.

[73] Assignee: American Home Products Corporation, New York, N.Y.'

22] Filed: Sept. 6, 1973 21 Appl. No.: 394,707

Related U.S. Application Data [60] Division of Ser. No. 757,792, Sept. 5, 1968, Pat. No. 3,763,178, which is a continuation-in-part of Ser. Nos. 622,918, March 14, 1967, and Ser. No. 622,931, March 14, 1967, and Ser. No 576,833, Sept. 2, 1966, and Ser. No. 487,587, Sept. 15, 1965,

abandoned.

[52] US. Cl. 260/309.6, 260/296 T [51] Int. Cl. C07d 49/34, C07d 57/02 [58] Field of Search 260/309.6

[56] References Cited OTHER PUBLICATIONS Sulkowski et al., Journ, Org. Chem, 32, 1967, pp. 2l80-2l84.

Primary Examiner-Lewis Gotts Assistant ExaminerEthel G. Love Attorney, Agent, or FirmStephen Venetianer; Vito Victor Bellino [5 7] ABSTRACT 4 Claims, No Drawings This is a division of application Ser. No. 757,792, filed Sept. 5, 1968, now U.S. Pat. No. 3,763,178 which in turn is a continuation-in-part of US. Pat. applica tions, Ser. No. 622,918, entitled Tetrahydropyrimidinyl Phenyl Carbonyl and Imidazolinyl Phenyl Carbonyl Compounds, filed Mar. 14, 1967; Ser. No. 622,931, entitled Process For the Preparation of imidazolinyl Phenyl Carbonyl Compounds," filed Mar. 14, 1967; Ser. No. 576,833, entitled 2-(3- Aminopropyl)lsoindoles and Related Compounds, filed Sept. 2, 1966; and Ser. No. 487,587, entitled 1,2- ,3,4,6,lb-Hexahydropyrimido[2,l-a]lsoindol-6-Ones and Related Compounds," filed Sept. 15, 1965 and now abandoned.

This invention relates to bicylic and tricyclic nitrogen containing compounds as well as to novel methods for their preparation. In particular, the present invention is concerned with tetrahydropyrimidinyl phenyl carbonyl acid addition salts, tetrahydropyrimidoisoindolols and tetrahydropyrimidoisoindolol acid addition salts which in standard and accepted pharmacological tests have demonstrated both anti-depressant and diuretic activities. Further, it is concerned with imidazolinyl phenyl carbonyl acid addition salts and dihydroimidazoisoindolols which in standard and accepted pharmacological tests have demonstrated both anti-depressant and anorexiant activities.

The new and novel compounds which are included within the scope of this invention are represented by the following formulae:

and

(III) wherein R and R are selected from the group consisting of hydrogen, lower alkyl, phen(lower )all yl, phenyl, monohalophenyl, dihalophenyl, mono(lower)alkylphenyl, di(lower)alkylphenyl, trifluoromethylphenyl, mono(lower)alkoxyphenyl, di(lower)alkoxyphenyl,

thienyl, pyridyl, fury] and tetrahydro-Z-naphthyl, with the provision that R, is hydrogen, lower alkyl and phen(lower)alkyl when n is 2; R is selected from the group consisting of hydrogen, halogen, amino, lower alkylamino, lower alkyl and lower alkoxy; R is hydrogen when R and R are dissimilar and when R and R are the same they are both selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy; R is selected from the group consisting of phenyl, monohalophenyl, dihalophenyl, mono(lower)alkylphenyl, di(lowcr)alkylphenyl, trifluoromethylphcnyl, mono(lower)alkoxyphenyl, di(lower)alkoxyphenyl, thienyl, pyridyl, fury] and tetrahydro-2- naphthyl; n is an integer from I to 2; and HX is a pharmacologically acceptable acid addition salt. As employed herein the terms lower alkyl," lower alkoxy" and the like are meant to include both branched and straight chain moieties containing from one to about six carbon atoms.

The new and novel compounds of this invention which are represented by structural formula (I) wherein n is l are called imidazolinyl Phenyl Carbonyl Acid Addition Salts." Typical examples thereof are: 2(2-imidazolin-2-yl) benzophenone hydrochloride and 4'-chloro-2-(2-imidazolin-2-yl)benzophenone hydrochloride. Alternatively, those compounds of structural formula (I) wherein n is 2 are named: Tetrahydropyrimidinyl Phenyl Carbonyl Acid Addition Salts," such as, 2- (3,4,5,6-tetrahydro-2-pyrimidinyl)-4- methylbutyrophenone hydrochloride and 2-phenyl-2- (3,4,5,6-tetrahydro-2-pyrimidinyl)acetophenone hydrochloride.

The new and novel compounds of this invention which are depicted by structural formula (II) wherein n is l are designated Dihydroimidazoisoindolols, for example, 2,3-dihydro-5-phenyl-5H-imidazo[2,la]isoindol-5-ol and 5-(4-chlorophenyl)-2,3-dihydro- 5H-imidazo[2,l-a]-isoindol-5-ol. Alternatively, those compounds ofstructural formula (11) wherein n is 2 are called Tetrahydropyrimidoisoindolols, such as, 6-(4- chlorophenyl)-2,3,4,6-tetrahydropyrimido[2,1- a]isoindol-6-ol and 2,3,4,6-tetrahydro-6- phenylpyrimido[2,l-a]isoindol-6-ol.

The new and novel compounds of this invention which are represented by structural formula (III) are named Tetrahydropyrimidoisoindolol Acid Addition Salts. Typical examples thereof are: 6-(4- chlorophenyl)-2,3,4,6-tetrahydropyrimido[2,1- a]isoindol-6-ol hydrochloride and 2,3,4,6-tetrahydro 6-phenylpyrimido"2,l-a]isoindol-6-ol hydrochloride.

In accord with the new and novel first process of this invention, the tetrahydropyrimidoisoindolols of this invention may be produced by the oxidation of 2 (3- aminopropyl)isoindoles, as exemplified by the follow- -Oll R4 wherein R R and R are defined as above. Various oxidation processes will readily suggest themselves to those skilled in the art. For example, the particular 2-(3-aminopropyl)isoindole (A) may be dissolved in a reaction-inert solvent, e.g. an alkanol, and purged with oxygen or air until the oxidation is complete. Alternatively, the oxidation may be accomplished by contacting the 2-(3-aminopropyl) isoindole solution with an oxidzing agent, such as potassium dichromate, potassium chlorate, or potassium permanganate. The oxidawherein R R and R are defined as above, R is aryl and alkyl, for example: lower alkyl, phenyl, monohalophenyl, dihalophenyl, mono(lower )alkylphenyl, di(lower)alkylphenyl and alkoxyphenyl, and X is the anion portion ofa mineral acid. The rearrangement of a tetrahydroimidazoisoindolone of formula l is effected by contacting the particular compound l) with a mineral acid. This reaction may be accelerated by heating and stirring the reaction mixture until the precipitation of the 2-(aminoethyl)-3- wherein R is selected from the group consisting of hydroxyphthalimidine mineral acid addition salt, as designated in formula (2), is complete. The phthalimidine (2) is separated by filtration or decantation and either recrystallized from a suitable solvent, such as water, a lower alkanol and dioxan, or admixed directly with a substantially equimolar quantity of an aryl or alkyl sulfonyl halide in pyridine. The reaction mixture is then heated to a temperature from about C.. to about 115C. for a period from about 2 hours to about 10 hours. Preferably, this reaction is conducted at the reflux temperature of the reaction mixture for a period of about two hours. After the above reaction is complete, the product of sulfonyltetrahydroimidazoisoindolone (3) is recovered by customary isolation procedures.

The above prepared sulfonyltetrahydroimidazoisoindolone (3) may be hydrolyzed and rearranged by admixture with from about 80 to about percent sulfuric acid. The product of this hydrolysis, the sulfate salt of an imidazolinyl phenyl carbonyl compound, as shown in formula (4) which may be recovered as such by conventional means. Alternatively, the reaction mixture is neutralized by the addition of a base and the resulting precipitate recrystallized from an appropriate organic solvent such as lower alkanol. dioxan, dimethylformamide and dimethylacetamide to afford an appropriate dihydroimidazoisoindolol (5).

As a new and novel alternative to the second process of the present invention, it has been found that the dihydroimidazoisoindolols of this invention may also be prepared by directly reacting a tetrahydroimidazoisoindolone (1) with an aryl or alkyl sulfonyl halide under the above-described reaction conditions to afford an appropriate sulfonyltetrahydroimidazoisoindolone (3 Thereafter, this compound (3) is further reacted as hereinbefore described to yield an imidazolinyl phenyl carbonyl sulfate salt (4) which may then be neutralized to afford a dihydroimidazoisoindolol (5).

As a further alternative to the second process of the present invention, it should be noted that the 2.- (aminoethyl)r3-hydroxyphthalimidine (2) intermediates can also be prepared by the condensation of an acid chloride of an o-earbonyl benzoic acid with ethylene diamine as described by Sulkowski et al. in J. Org. Chem. 32, 2180 (1967).

' In accord with the new and novel third process of the present invention, some of the dihydroimidazoisoindolols of this invention may be prepared by the procedure which is exemplified by the following reaction scheme: I

N I l m N In {Y .[o N

l/ l lil In N R0 lower alkyl, phenyl, lower alkylphcnyl, lower alkoxyphenyl, di(lower)alkylphenyl, di(lower)alkoxyphcnyl, aminophenyl, trifluoromethylphenyl, monohalophenyl. dihalophenyl, furyl, thienyl and naphthyl; R is selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy; R is hydrogen when R, and R are dissimilar and when R and R are the same they are both selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy.

The oxidation reaction is effected by contacting an appropriate h exahydrobenzodiazocine (a) with an oxidizing agent in a reaction-inert solvent at a temperature fromabout C. to about 60C. for a period of about one-half to about four hours. Preferably, this reaction is conducted by contacting an aqueous solution of a hexahydrobenzodiazocine salt with a potassium permanganate solution at room temperature for about one hour. Many other oxidizing agents and reaction-inert solvents which may be employed in this reaction will readily suggest themselves to those skilled in the art. In this regard. excellent results can be obtained when potassium dichromate and potassium chlorate are employed as the oxidizing agents. By reaction-inert solvent as employed herein is meant a solvent which will dissolve the hexahydrobenzodiazocine and not interfere with the oxidation reaction, such as, water while acetone and methyl ethyl ketone may be employed as solvents when potassium permanganate is employed as the oxidizing agent.

When the oxidation reaction is complete, the corresponding dihydroimidazoisoindolol (b) may be separated and recovered by routine means, for example, precipitating the product by the addition of a base and then separating it by decantation or filtration. The time and temperature ranges employed in the aforesaid reactions are not critical but simply represent the most convenient range consistent with carrying out these reactions in a minimum of time without undue difficulty. Thus reaction temperatures appreciably below these can be used, but their use considerably extends the reaction time. Similarly, reaction temperatures higher than those mentioned can be employed with a concomitant decrease in reaction time. The 2-(3 aminopropyl)isoindoles (A) employed as starting materials in the first above described process for the preparation of the tetrahydropyrimidoisoindolol compounds (B) of this invention are known compounds which are described in co-pending U.S. Pat. application, Ser. No. 622,917, entitled Isoindoles, Isoindolines and Related Compounds, filed on Mar. 14, 1967, by Theodore S. Sulkowski which is a continuation-inpart of U.S. Pat. applications, Ser. No. 576,833, entitled 2-(B-AminopropylJlsoindoles and Related Compounds, filed Sept. 2, 1966 and Ser. No. 487,587, entitled 1,2,3,4,6,lOb-hexahydropyrimido 2,1- a]1soindol-6 0nes, filed September 15, 1965 and now abandoned. The tetrahydroimidazoisoindolones (l) and the hexahydrobenzodiazocines (a) which are respectively employed as starting materials in the second and third above described process for the preparation of the dihydroimidazoisoindolols (5) of this invention are known compounds which are described in copending U.S. Pat. application, Ser. No. 609,779, entitled Benzodiazocines,-filed on Jan. 17, 1967, by Theodore S. Sulkowski, which is a continuation-in-part of U.S. Pat. applications, Ser. No. 554,672, entitled Benzodiazocines," filed on June 2, 1966; Ser. .No. 444.050, entitled Substituted 3,4-Dihydro-6-Aryl-2.5- Benzodiazocin-l (2H)-Ones and Related Compounds," filed on Mar. 30, 1965 and now abandoned; and Ser. No. 272,216, entitled Substituted 3,4-Dihydro-6- Aryl-2,5-Benzodiazocin-l(2H)-Ones and Related Compounds, filed on Apr. 11, 1963 and now abandoned. The aryl or alkyl sulfonyl chlorides used in this latter process are well known chemicals which are commercially available or may easily be prepared by well known chemical procedures.

The tetrahydropyrimidoisoindolols (B) of the present invention were at first thought to be Hexahydropyrimidoisoindolones" and were so described in the first prior tiled parent application (U.S. Ser. No. 487,587). Subsequently, these cmpounds were re examined and then thought to be Tetrahydropyrimidinyl Phenyl Carbonyl Compounds and were so defined in the following two subsequently filed parent applications (U.S. Ser. No. 576,833 and 622,918). It has now been concluded, based on the nature of the starting materials; the mode of synthesis; the elemental analysis; and the ultra violet and infra red spectrographic analyses, that all the solid bases prepared by the first process of this invention are Tetrahydropyrimidoisoindolols (B). Further, since these nitrogen containing tetrahydropyrimidoisoindolols are basic in nature they will react with pharmacologically acceptable acids to form acid addition salts. Such acids are well known in the art, for example, hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric, phosphoric, acetic, lactic, citric, tartaric, maleic, gluconic, benzenesulfonic, toluenesulfonic, methylsulfonic, ethylsulfonic acids and the like. These salts may be preparedby procedures commonly employed in the art, for example, reacting the compound with an equivalent of the selected acid in aqueous solution andconcentration of the solution. Other known procedures may also be employed, e.g., the procedure of Example-VIII.

The ultra violet spectrographic analyses of the tetrahydropyrimidoisoindolols (B) of this invention and their acid addition salts which are substituted in the 6- position with an aromatic group, e.g. phenyl, monohalophenyl, dihalophenyl, mono(lower)alkylphenyl, di(lower)alkylphenyl, trifluoromethylphenyl, mono(lower)alkoxyphenyl, di(lower) alkoxyphenyl, thienyl, pyridyl, furyl and tetrahydro-2-naphthyl, demonstrate an absence of absorption in the 250 my. region indicating that both the bases and'salts possess these tetrahydropyrimidoisoindol structures in solution. Alternatively, ultra violet analyses of neutral and acidic solutions of these tetrahydropyrimidoisoindolols (B) and their acid addition salts which are unsubstituted, e.g. hydrogen or substituted in the 6-position with an aliphatic or aralkyl group, e.g. lower alkyl. and phen(- lower)alkyl demonstrate absorption in the 235 240 my. region indicating that their structures in solution are predominately the tetrahydropyrimidinyl phenyl carbonyl compounds of the structure:

R wherein R and R are defined as above and R is hydrogen, lower alkyl and phen(lower)alkyl. Further, the

infra red spectrographie analyses of these latter compounds determined by the procedure of Hofmann et al., Analyt. Chem, Vol. 39, pg. 406 (1967) also indi-.

cates that the solid acid addition salts thereof also exist in the above shown tetrahydropyrimidinyl phenyl carbonyl forms.

The dihydroimidazoisoindolols of the present invention were first thought to be Tetrahydroimidazoindolones and were so described in the first prior filed parent application. Subsequently, these compounds were re-examined and then thought to be Imidazolinyl Phenyl Carbonyl Compounds and were so defined in the following three subsequently filed parent applications (U.S. Ser. Nos. 576,833, 622,931 and 622,918). It has now been concluded, based on the nature of the starting materials; mode of synthesis; the elemental analysis; and ultra violet and infra red analyses, that all the solid bases prepared by the second and third process of this invention are "Dihydroimidazoisoindolols (5). Further, since these nitrogen containing dihy droimidazoisoindolos are basic in nature they also will react with pharmacologically acceptable acids as described above to form acid addition salts.

The ultra violet spectrographic analyses of the dihydroimidazoisoindolols (5) of this invention in neutral solution demonstrate an absence of absorption in the 250 mp. region .indicating that these bases also possess these dihydroimidazoisoindolol structures when they are dissolved in a non-acidic solution. Alternatively, the ultra violet analyses of acid solution of these bases and the neutral solutions of their acid addition salts demonstrate absorption in 250 mp. region indicating that they are imidazolinyl phenyl carbonyl compounds in solution of the structure:

where R R and R are defined as above. The infra red spectrographic analyses of these compounds also indicates that the solid bases are dihydroimidazoisoindolols while their corresponding solid acid addition' salts exist in the above shown imidazolinyl phenyl carbonyl forms.

The tetrahydropyrimidinyl phenyl carbonyl acid addition salts (formula I where n is 2);, the tetrahydropyrimidoisoindolols (formula II where n is 2); and the tetrahydropyrimidoisoindolol acid addition salts (formula III) of the present invention have been foundto possess valuable pharmacological activity. More particularly, these compounds have exhibited utility, in

' standard pharmacological tests, as anti-depressant and diuretic agents.

In the pharmacological evaluation of the antidepressant property of these compounds (I, n=2; II,

n=2; and III), the in vivo anti-depressant activity is evaluated by the procedure described by Rubin et al., in .l.P.E.T. 120, 125 (1957). When tested by this procedure, these compounds demonstrate useful antidepressant activity, e.g. having mood elevating properties as psychic energizers, when they are administered orally to mice in a dosage range from about 1 to about 100 mg./kilo of animal body weight. Further, the in vivo diuretic activity of these compounds (I, n=2; lI, n=2; and III) is evaluated by the procedure described by Lipschitz et al., in J. Pharmacol. 79, 97 (1943). When tested by this procedure these compounds'demonstrate useful diuretic activity when they are administrated orally to rats in a dosage range from about 0.25 to about 25 m g. /k ilo of animal body weight.

' depressant property of these compounds (I, n=l and II,

n=l the in vivo anti-depressant activity is also evaluated by the procedure described by Rubin et al., in J.P.E.T. I20, (1957). When tested by this procedure, these compounds demonstrate useful antidepressant activity, e.g. having mood elevating properties as psychic energizers, when they are administered orally to mice in a dosage range from about I to about 5 mg./kilo of animal body weight. Further, the in vivo anorexiant activity of these compounds (I, n=l and Il, n=l e.g. appetite suppressant effects is evaluated by the following procedure:

Male Charles River rats between l20 and grams are trained to drink sweetened condensed milk from a graduated drinking tube. After a short learning period the animals are placed on a routine of water ad lib for 24 hours, standard laboratory chow for 22 hours and sweetened condensed milk for 2 hours. The volume of milk consumed is measured at /2 hour as well as 2 hours and the animals are weighed daily. This schedule is maintained 5 days a week over a period of several months. Trials are run on the same day each week and changes in milk consumed and 24 hour weight changes are compared to the average of the 2 days before the test compound is administered. Animals are tested as groups of six and one group is given saline each week to serve as controls. The test compounds are usually administered intraperitoneally in saline and/or orally in YYlS The imidazolinyl phenyl carbonyl acid addition salts and the dihydroimidazoisoindolols of this invention in the above test procedure when administered orally to rats at a dose of 10 mg./kg. induce a decrease in food consumption of about 40 percent in the first half hour and about 20 percent in 2 hours with a concurrent total average weight loss of about /2 gram/animal in 24 hours. When administered intraperitoneally at a dose of 10 mg./kg., these compounds (I, n=l and II, n=l) induce a decrease in food consumption of about 80 percent in the first half hour and about'65 percent in 2 hours with a concurrent total 24 hour average weight loss of about 7%. grams/animal.

When the tetrahydropyrimidinyl phenyl carbonyl acid addition salts; .the tetrahydropyrimidoisoindolols and the tetrahydropyrimidoisoindolol acid addition salts of this invention are employed as anti-depressant and diuretic agents and when the imidazolinyl phenyl dihydroimidazoisoindolols of this invention are employed such excipients as starch, milk sugar, certain types of clay and so forth. They may also be administered orally in the form of solutions or they may be injected parenterally. For parenteral administration they may be used in the form of a sterile solution containing other solutes. for example, enough saline or glucose to make the solution isotonic.

The dosage of the compounds of this invention will vary with the form of administration and the particular compound chosen. Furthermore, it will vary with the particular subject under treatment. Generally, treatment is initiated with small dosages substantially less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. In general, the compounds of this invention are most desirably administered at a concentration level that will generally afford effective results without causing any harmful or deleterious side effects.

The following examples are given by way of illustration and are not to be construed as limitations of this invention, many variations of which are possible without departing from the scope and spirit thereof.

EXAMPLE I The 2-(3-aminopropyl)-1-(4-chlorophenyl)- isoindole, hydrochloride (2 gms.) is dissolved in water and neutralized with a sodium carbonate solution. The regenerated base is extracted with ethyl acetate, dried over magnesium sulfate and evaporated to drynes s fThe residue is dissolvedin 250 ml. of ethanol and air is bubbled through the solution for 48 hours. The precipitated white crystalline solid is separated by filtration .and upon recrystallization from dimethylformamide t re is obtained 6-(4-chlorophenyl)-2,3,4,6- tet rahydropyrimido[2, l-a]-isoindol-6-ol, mp.

2-(3- PRODUCTS AMINOPROPYLHSOINDOLES 2-( 3-aminopropyl )-6-bromol (4-toly|)isoindole 2 3-aminopropyl )-5-methyll propylisoindole 2-(3-aminopropy1) 4-iodoisoindole 2 3-aminopropyl 1 -(4 bromophenyl )-5 .b dibromoisoindole 8-bromo-2.3.4.6-tetrahydro- 6 (4tolyl )Pyrimido[2, l-a] isoindol-6-ol 2.3.4.6-tetrahydro-9- methyl-6-propylpyrimido [2, l-alisoindol-6 ol 2.3.4.6tetrahydro-10- iodopyrimidol 2.1-alisoindol 6-ol 8.9-dibromo-6-( 4-bl'01110- phenyl )-2.3.4.6-tetrahydropyrimido[ 2. l -a]isoindol- 6-01 2.3,4,6-tetrahydro-6-(2.4- dimethoxyphenyl)pyrimido [2,1-a]isoindo1-6-o1 2746C. dec., which is insoluble in water and soluble in dimethylacetamide.

Analysis: Ultra Violet Absorption (95 ETOH) max. 224 mp. (F 23,000), infl. 243 mp. (F 12,000), max. 267 mp.(e= 3,800); Ultra Violet Absorption (pHl) max. 223 mp.(e= 21,100), int]. 243 mp. (5 14,200), max. 267 me (e=3,800); Infra Red Absorption (KBr) 1,652 cm 2,400-3,000 cm.

Calcd for C H CIN O: C, 68.33; H, 5.06; N, 9.33; Cl, 11.87 Found: C, 68.12; H, 5.39; N, 9.22;C1, 11.85.

The above prepared tetrahy dropyrimidoiso indolol is dissolved in ethanol and admixed with an aqueous solution containing an equivalent amount of hydrochloric acid. The mixture is stirred for ten minutes and the sol vent removed by evaporation. In this manner, is ob- EXAMPLE 111 Ten grams of IOB-phenyl-l,2,3,4,6,10b-hexahydropyrimido[2,1-a]isoindol-6-one are added in portions to a stirred suspension of 2.5 grams of lithium aluminum hydride in 250 m1. of anhydrous ether. The mixture is stirred and refluxed for one hour, then the excess hydride is decomposed by careful addition of water. The ether layer is separated, dried over magnesium sulfate and evaporated to dryness. Without isolation or further purification, the 2-(3-aminopropyl)-lphenylisoindole is dissolved in 200 ml. of ethanol and oxygen is bubbled through the solution for 48 hours. The precipitated solid is separated'by filtration and on recrystallization from dimethylformamide there is obtained 2,3,4,6-tetrahydro-6-phenylpyrimido[2.la]isoindol-6-ol, m.p. 2557C. dec.. as white prisms which is insoluble in water and slightly soluble in hot dimethylacetamide.

Analysis: Ultra Violet Absorption ETOH) max. 233 mp (e 14,000), max. 268 mu (6 4,000), infl. 271 mp. (e 3,000); Ultra Violet Absorption (pHl) max. 239 mp. (s 14,900), infl. 271 mu (6 3,000), Infra Red Absorption (KBr) 1,650 cm", 2,3003,000 cm.

Calcd for C H -N O: C, 77.25; H, 6.10; N, 10.60. Found: C, 77.36; H, 6.05; N, 10.51.

The above reaction is repeated in anhydrous diisopropyl ether at 60C. for 2 hours with similar results.

In a similar manner, starting with l0b-(3',4'- dichlorophenyl)-1,2,3,4,6,l0b-hexahydropyrimido[2,l-alisoindol-6-one there is obtained 6- (3 ,4-dichlorophenyl )-2,3 ,4,6-tetrahydropyrimido[2,1-

alisoindol-6-ol, m.p. 2679C., as a white crystalline solid which is insoluble in water and slightly soluble in hot dimethylacetamide.

Analysis: Ultra Violet Absorption (95 ETOH) infl. 230 mp (e 22,600), max. 268 mp (e 4,500); infl. 282 mp. (e 2,000); Ultra Violet Absorption (pHl) max. 228 mp. (e 22,000), max. 268 mp (e 4,700); infl. 282 mp. (e 1,600); Infra Red Absorption (KBr) 1,650 cm", 2,3003,000 cm.

Calc'd for C H Cl N O: C, 61.27; H, 4.24; N, 8.41; CI, 21.29. Found: C, 61.41; H, 4.28; N, 846; C1, 21.2.

EXAMPLE IV Violet Absorption (pHl) max. 229 mp. (e 21,500),

max. 267 mp (6 4,300); Infra Red Absorption (KBr) 1,645 cm, 2,300-2,900 cm".

C-alcd for C,' H BrN O: C, 59.48; H, 4.41; N, 8.16. Found: C, 59.51; H, 4.36; N, 8.26.

Similarly, utilizing anhydrous ethylene glycol dimethyl ether as the solvent, 6-(2,4-dibromophenyl)- 2,3,4,6-tetrahydropyrimido[2,1-a]isoindo1-6-ol is synthesized.

EXAMPLE V benzene and oxidized by bubbling oxygen through the solution for 60 hours. The precipitate is separated by filtration and recrystallized from dimethylacetamide. In this manner, is obtained 6-(5,6,7,8-tetrahydro-2- naphthyl)-2,3,4,6-tetrahydropyrimido[2, l-alisoindol- 6-01, m.p. 253-5C. dec., as a white crystalline solid I which is insoluble in water and soluble in hot dimethylacetamide.

Analysis: Ultra Violet Absorption (95% ETOH) infl. 230 mp. (e 10,000), infl. 245 mp (e 9,200), max. 270 mp (e 3,200); Ultra Violet Absorption (pH) infl. 230 mp (e= 10,900), infl. 245 m;L (e 10,000), max. 270 mp (e 3,200); Infra Red Absorption (KBr), 1,655 cm", 2,300-3,000 cm.

Calcd for C H N O: C, 79.21; H, 6.96; N, 8.80.

Found: C, 78.96 H, 7.15 N, 8.95.

In a similar manner, 6-(4-trifluoromethylphenyl- 2,3,4,6-tetrahydropyrimido[2,1-a]isoindo1-6-ol; 6-(2- trifluoromethylphenyl)'2,3,4,6- tetrahydropyrimido[2,l-alisoindol-6-ol; and 6-furyl- 2 ,3,4,6-tetrahydropyrimido[ 2, l -a]isoindo1-6-ol are produced.

EXAMPLE V1 Analysis: Ultra Violet Absorption ETOH) max. 236 mp. (e= 12,600), infl. 265 mp. (e 4,100); Ultra Violet Absorption (pH4) max. 239.5 mp (e 14,200), infl. 265 mp (B 4,100); Infra Red Absorption (KBr), 1,640 cm, 2,3003,000 cm; Infra Red Absorption of the in situ hydrochloride salt by the procedure of Hofmann et a1., Analyt. Chem. Vol. 39, pg. 406 (1967) (KBr) 1,670 cm, 1,647 cm, 2,6003,100 cm.

Calcd for C H N O: C, 71.26; H, 6.98 N, 13.87. Found: C, 71.30; H, 6.90; N, 13.63

In a similar manner, the following compounds are prepared:

2,3,4,6-Tetrahydropyrimido[2,1-a]isoindol=6-ol, m.p. 205-7C., as a white crystalline sold which is insoluble in water and slightly soluble in dimethylacetamide.

Analysis: Ultra Violet Absorption (95% ETOH) max. 235 mp. (6 12,400), infl. 266.5 mp. (e 3,650); U1tra Violet Absorption (pHl) max. 240 mp. (e 10,800), infl. 266.5 mp (e= 3,650); Infra Red Absorption (KBr) 1,640 cm, 2,3003,000 cm; Infra Red Absorption of the in situ hydrochloride by the above-identified procedure (KBr) 1,670 cm, 2,600-3,l00 cm.

Calcd for C H N O: C, 70.18; H, 6.42; N, 14.88.

Found: C, 69.92; H, 6.47; N, 14.71.

6-Benzyl-2,3,4,6-tetrahydropyrimido[2,l-a]isoindol- 6-01, m.p. 233.5C. dec., as a white crystalline solid which is insoluble in water.

Analysis: Ultra Violet Absorption (95% ETOH) max. 235 mp. (e= 11,700), infl. 269 mp. (e 3,900); Ultra Violet Absorption (pHl) max. 240 mp (e 12,900), infl. 269 mp. (e 3,900); Infra Red Absorption (KBr) 1,645 cm' 2,3003,000 cm; Infra- Red Absorption of the in situ hydrochloride by the above-identified procedure (KBr) 1,665 cm, 2,6003,100 cm.

Calcd for C H N O: C, 77.66; H, 6.52; N, 10.07. Found: C, 77.67; H, 6.41; N, 9.77.

6-Butyl-2,3,4,6-tetrahydropyrimido[2,l-a]isoindol- 6-01, m.p. 18l3C., as a white crystalline solid which is insolube in water and soluble in ethanol and dimethylacetamide.

Analysis: Ultra Violet Absorption (95% ETOH) max. 234.5 mp. (e 12,100), infl. 266 mp. (e= 4,000); Ultra Violet Absorption (pHl) max. 240 mp. (e 14,000), infl. 266 mp. (e 4,000); Infra Red Absorption (KBr) 1,640 cm, 2,300-3,000 cm; Infra Red'Absorption of the in situ hydrochloride by the above-identified procedure (KBr) 1,670 cm, 1,640 cm", 2,600-3,100 cm Calcd for C H N O: C, 73.73; H, 8.25; N, 11.47. Found: C, 74.03; H, 7.99; N, 11.63.

6-(3-Amino-4-ch1orophenyl)-2,3,4,6-

tetrahydropyrimido[2,l-a]isoindol-6-ol, m.p.

2278C. dec., as a white crystalline solid which is in- EXAMPLE V11 When the procedure of the aforementioned Examples is employed, the hereinafter listed 2-(3- 2-(3,4,5,6-tetrahydro-2-pyrimidinyl)-2-methyl-4,5-

dipropoxypropiophenone hydrochloride; 6-(3,4-diethoxyphenyl)-2,3,4,6-

tetrahydropyrimido[2,l-a]isoindol-6-o1 hydrochloride; 6-(4-hexylphenyl)-2,3,4,6-tetrahydropyrimido[2,1- a]isoindol-6-ol hydrochloride; 4-amino-2-(3,4,5,6-tetrahydro-2- pyrimidinyl)benzaldehyde dihydrochloride; 9-ch|oro-6-(4-ethylphenyl)-2,3,4,6-

tetrahydropyrimido[2,l-a]isoindol-6-ol hydrochloride; 2,3,4,6-tetrahydro-6-(2-thienyl)pyrimido[2,1-

alisoindol-6-ol hydrochloride; 2,3,4,6-tctrahydro-9-methyl-6-pheny|pyrimido[2,1-

alisoindol-6-ol hydrochloride; 2,3,4,6-tetrahydro-6-phenyl-7-propylpyrimido[2,l-

a]isoindol-6-ol hydrochloride; 6-(4-fluorophenyl)-2,3,4,6-tetrahydropyrimido[2,l-

a]isoindol-6-ol hydrochloride; 6-(3-bromo-4-methylphenyl)-2,3,4,6-

tetrahydropyrimido[2,1-a]isoindol-6-ol hydrochloride; 2,3,4,6-tetrahydro-6-( 3-iodophenyl )pyrimido{ 2, l

a]isoindol-6-ol hydrochloride; 9-amyl-2,3 ,4,6-tetrahydro-6-phenylpyrimido 2, l

a]isoindol-6-ol hydrochloride; 2,3,4,6-tetrahydro-6-phenyl-8- propylaminopyrimido[2,l-a]isoindol-6-ol dihydrochloride; 9-butoxy- 2,3 ,4,6-tetrahydro-6-phenylpyrimido 2, l

a]isoindol-6'-ol hydrochloride; 2,3,4,6-tetrahydro-6-(3,4-

dimethylphenyl)pyrimido12,l-a]isoindol-6-ol hydrochloride; 2,3,4,6-tetrahydro-6-(4- propoxyphenyl)pyrimido[2,1-a]isoindol-6-ol drochloride; 2-(3,4,5,6-tetrahydro-2-pyrimidinyl)-4,5-dimethyl- Y benzaldehyde hydrochloride; 2,3,4,6-tetrahydro-6-pyridylpyrimido[2,l-a]isoindol- 6-ol hydrochloride; and 2-(3,4,5,6-tetrahydro-2-pyrimidinyl)-4- methoxyvalerophenone hydrochloride.

EXAMPLE X Thirty-five grams of 9b-(p,-chlorophenyl)-l,2,4,9b-

tetrahydro-lH-imidazo[2,l-a]isoindol--one and 150 ml. of.60 percent hydrochloric acid are stirred and heated to a clear solution. Stirring is continued for 20 minutes after solid begins to precipitate. The mixture is cooled and the solid is separated by filtration. On recrystallization from ethanol there is obtained 2-(2- aminoethyl)-3-(p-chlorophenyl)-3- hydroxyphthalimidine hydrochloride, m.p. 243-5C.

Analysis: Calcd for C H N OCLHCl: C, 56.63; H, 4.76; N, 8.26; Cl, 20.91. Found: C, 56.38; H, 4.57; N, 8.01; Cl, 20.9.

Seventeen grams of the phthalimidine hydrochloride from above. 20 g. of p-toluenesulfonyl chloride and 200 ml. of pyridine are refluxed for two hours and then the mixture is evaporated to dryness. On recrystallization of the residue from ethanol there is obtained 9b- (p-chlorophenyl)-l,2,3,9b tetrahydro-1-(p tolylsulfonyl)-lH-imidazo[2,l-a]isoindol-5-one, m.p. 1702C.

Analysis: Calcd for C H, ClN O S: C, 62.93; H, 4.34; N, 6.38; CI, 8.08; S, 7.30. Found: C, 63.24; H, 4.61; N, 6.15; Cl, 7.91; S, 7.3.

Ten grams of 9b-(p-chlorophenyl)-l,2,3,9btetrahydro-l-(p-tolylsulfonyl)-1H-imidazo[2,la]isoindol-5-one are dissolved in 25 ml. of 90 percent sulfuric acid and stirred at room temperature for onehalf hour. The solution is quenched with ice water, then filtered to separate some precipitated solid. The filtrate which contains the sulfate salt of 4-chloro-2-(2- imidazolin-2-yl)benzophenone is cooled and made 0 max. 251 mp. (e-,- 11,000), max. 253 mu (e= 10,800);

Infra Red Absorption (KBr) 1,647 cm, 2,3003,20O cm.

Calcd for C ,,H N OCl: C, 67.49; H, 4.60; N, 9.40; Cl, 12.45. Found: C, 67.18; H, 4.32; N, 9.68; Cl, 12.7.

In a similar manner, the sulfate salts of 2-(2- imidazolin-2-yl)-3,4-diiodobenzophenone; 2-(2- imidazolin-2-yl)-2-methyl-4",5-dipropoxypropiophenone and 3,4-diethoxy-2-(2-imidazolin-2- yl)benzophenone are produced which are then contacted with a saturated sodium bicarbonate solution to respectively afford the following compounds: 2,3--

dihydro-5-(3,4-diiodophenyl)-5H-imidazo[2,lalisoindol-S-ol; 2,3-dihydro-5-isopropyl-7,8 dipropoxy-5H-imidazo[2,l-a]isoindol-5-ol; and 5-(3,4- diethoxyphenyl)-2,3-dihydro-5H-imidazo[2,1- a]isoindol-5-ol.

EXAMPLE X1 Seventy grams of 9b-(p-tolyl)-l,2,3,9b-tetrahydrolH-imidazo[2,l-a]isoindol-5-one and 300 ml. of 48 percent hydrobromic acid are stirred and heated to a clear solution. Stirring is continued for fifteen minutes after precipitation. Thereafter, the reaction mixture is cooled and the precipitated solid, 2-(2-aminoethyl) 3- (p-tolyl)-3-hydroxyphthalimidine hydrobromide, is separated by decantation, admixed with 40 g. of ptoluenesulfonyl chloride and 400 ml. ofpyridine, heated to 100C. for 4 hours and evaporated to dryness.

Twenty grams of the residue 9b-(p-tolyl)-1,2,3,9btetrahydrol -(p-tolylsulfonyl l H-imidazo[2, 1 a]isoindol-5-one are dissolved in 50 ml. of 80 percent sulfuric acid and stirred at roomtemperature for one hour. The reaction mixture which contains the salt of 2(2-imidazolin-2-yl)-4'-'methylbenzophenone is then cooled by the addition of ice water and made alkaline by the addition of a ION sodium hydroxide solution. The precipitated solid is separated by decantation and recrystallized from dioxan to obtain crystalline 2.3-

l the imidazo[2,l-a]isoindo1-5-o1; 8-chloro-5-(4- ethylphenyl)-2,3-dihydro-H-imidazo[2,1-a]isoindol- 5'01; and 2,3-dihydro-5-( 2-thienyl )-5H-imidazo[2, l a]isoindol-5-ol.

EXAMPLE XII Thirty-five grams of 9b-phenyl-l,2,3,9b-tetrahydrolH-imidazo[2,l-alisoindol-S-one and 150 m1. of 50 percent hydrochloric acid are stirred and heated to a clear solution. Stirring is continued for 30 minutes after solid begins to precipitate. The mixture is cooled and the solid is separated by filtration. On recrystallization from ethanol there is obtained 2-( 2-aminoethyl)-3 phenyl-3-hydroxyphthalimidine hydrochloride.

Seventeen grams of the phthalimidine hydrochloride from above, 20 g. of p-butoxyphenylsulfonyl chloride and 200 ml. of pyridine are refluxed for two hours and then the mixture is evaporated to dryness. On recrystallization of the residue from ethanol there is obtained 9bphenyl-l ,2,3,9b-tetrahydro- 1 -(pbutoxyphenylsulfonyl)-1H-imidazo[2,1-a]isoindol- 5-one which is admixed with 25 ml. of 95 percent sulfuric acid for one hour. The reaction mixture which contains the sulfate salt of 2-(2-imidazolin-2-yl) benzophenone is then cooled by the addition of ice water and made alkaline by the addition of a 5N potassium hydroxide solution. The product is then separated by liltration and recrystallized from dioxan to afford 2,3- dihydro-5-phenyl-5H-imidazo[2,1-a]isoindol5-ol, mp. 207C., as a white crystalline solid which is insoluble in water and soluble in dimethylacetamide and ethanol.

Analysis: Ultra-Violet Absorption (95% ETOH) infl. 225 mu (6 14,900), max. 268 mp. (e 4,200); Ultra Violet Absorption (pH 1) max. 250 mu (6 13,500); Infra Red Absorption (KBr) 1,660 cm, 2,300-3,000 cm.

Calcd for C H N O: C, 76.77; H, 5.63; N, 11.20. Found: C, 76.63; H, 5.66; N, 11.0.

Similarly, the sulfate salts of 2-(2-imidazo1in-2-y1)-4- methylbenzophenone and 2-(2-imidazolin-2-yl)-6- propylbenzophenone are produced which are then converted to 2,3-dihydro-8-methyl-5-phenyl-5H- imidazo[2,1-a]isoindol-5-ol and 2,3-dihydro-5-phenyl- 6-propyl-5H-imidazol2,1-a]isoindol-5-ol.

EXAMPLE XIII Forty grams of 9b-(p-bromophenyl)-1,2,3,9btetrahydro-lH-imidazo[2,l-a]isoindol-5-one and 200 ml. of 50 percent hydrochloric acid are stirred and heated to a clear solution. Stirring is continued for 20 minutes after solid begins to precipitate. The mixture is cooled and the solid is separated by filtration. On recrystallization from ethanol there is obtained 2-(2- aminoethyl)-3-(p-bromophenyl)-3- hydroxyphthalimidine hydrochloride.

Twenty grams of the phthalimidine hydrochloride from above, 24 g. of p-bromophenylsulfonyl chloride and 250 ml. of pyridine are refluxed for three hours and then the mixture is evaporated to dryness. On recrystallization of the residue from methanol there is obtained 9b-(p-bromophenyl)-l ,2,3 ,9b-tetrahydro-l-(pbromophenylsulfonyl)- 1 H-imidazo[2, l -a]isoindo1- 5-0ne which is hydrolyzed with sulfuric acid to afford sulfate salt of 4'-bromo-2-(2-imidazolin-2- yl)benzophenone which is contacted with an aqueous 'sodium hydroxide solution. The product is then sepa rated by filtration to afford 5-(4-bromophenyl)-2,3- dihydro-5Himidazo[2,l-a]isoindol-5-ol, m.p. 1946C.. as a white crystalline solid which is soluble in dimethylacetamide and hot ethanol.

5 Analysis: Ultra Violet Absorption (95% ETOH) max.

228 a (e= 15,300), max. 268 ,u (e=4,800), max. 274

t (e= 4,800); Ultra Violet Absorption (pHl max. 250 u (e 11,000), max. 270 ,u. (e=l0,500); Infra Red Absorption (KBr) 1,660 cm, 2,3003,000 cm- Calcd for C H N OBr: C, 58.38; H, 3.98; N, 8.50; Br, 24.28. Found: C, 58.25; H, 4.02; N, 8.46; Br, 24.00.

In a similar manner, the following compounds are prepared:

3',4-dichloro-2'-(2-imidazo1in-2-yl)benzophenone sulfate which is neutralized to afford 5-(3,4- dichlorophenyl)-2,3-dihydro-5H-imidazo[2,la]isoindo1-5-ol, m.p. 2035C., as a white crystalline solid which is soluble in hot dimethylacetamide and hot ethanol.

Analysis: Ultra Violet Absorption (95 /o ETOH), infl. 228 ,u. ($21,200), max. 274 ,u (e 4,500), max. 281;]. (e 3,500); Ultra Violet Absorption (pHl max. 243 p. (6 12,200), max. 251 ,u. (6 11,750), infl. 265 p. (=9,000), infl. 278 p. (e=6,750); Infra Red Absorption (KBr) 1,655 cm, 2,3003,000 cm.

Calcd for C H C1 N O: C. 60.21; H, 3.79; N, 8.78; Cl, 22.22.

Found: C, 59.91; H, 3.66; N, 8.66; Cl, 22.30.

4-fluoro-2-(2-imidazolin-2-yl)benzophenone sulfate which is neutralized to afford 5-(4-f1uorophenyl)-2,3- dihydro -5-H-imidazo[2,l-alisoindol-S-ol, m.p. 214-216C., dec., as a white crystalline solid which is insoluble in water and soluble in dimethylacetamide.

Analysis: Ultra Violet Absorption (95% ETOH), infl. 235 p.(= 12,000), infl. 242 ,u (e= 10,200), max. 263 ,u. (5 6,100), max. 268 1.1. (e=5,600); Ultra Violet Absorption (pHl) max. 251 (e 13,000); Infra Red Absorption (KBr) 1,640 cm, 2,3003,000 cm.

Calcd for C H N OF: C, 71.62; H, 4.88; N, 10.44. Found: C, 71.73; H, 5.00; N, 10.68.

3-bromo-4-methyl-2-(2-imidazolin-2- yl)benzophenone sulfate which is neutralized to afford 5-(3-bromo 4 methylphenyl)-2,3-dihydro-5H- imidazo[2,l-a]isoindol-5-ol, m.p. 233-5C., dec., as a white crystalline solid which is insoluble in water and soluble in dimethylacetamide.

Analysis: Calcd for C H BrN O: C, 59.47; H, 4.41; N, 8.16; Br, 23.28. Found: C, 59.75; H, 4.60; N, 8.32; Br, 23.23.

EXAMPLE XIV Ninety grams of 1,2,3,9b-tetrahydro-9b-phenyl-5H- imidazo[2,l-a]isoindol-5-one, g. of ptoluenesulfonyl chloride and 1 liter of pyridine are heated at reflux for 14 to 18 hours. The solution is evaporated in vacuo to dryness, the residue slurried with water and then separated by filtration. On recrystallization from ethanol there is obtained 90 g. of 9bphenyl-l,2,3,9b-tetrahydro-1-(p-tolylsulfonl)-5H- imidazo[2,1-a]isoindo1-5-one, m.p. 158160C.

Ninety grams of the above prepared sulfonamidc compound is dissolved in 200 ml. of sulfuric acid and is left at room temperature for two hours. The solution is diluted with two volumes of water and extracted with ether. The aqueous portion which contains the sulfate salt of 2-(2-imidazolin-2-yl)benzophenone is then neutralized with 50% sodium hydroxide solution while EXAMPLE xv Sixty grams of 9b-(4-chlorophenyl)-l ,2,3,9btetrahydro-H-imidazo[2,l-a]isoindol-5-one, 60 g. of p-toluene-sulfonyl chloride and 750 ml. of pyridine are heated at reflux for 14 hours. The reaction mixture is worked-up as described in Example XIV to obtain 70 g. of 9b-(p-chlorophenyl)-l,2,3,9b-tetrahydro-l-(p -tolysulfonyl)-5H-imidazo [2,l-a]isoindol-5-one, m.p. l69-l7lC. which can be recrystallized from ethanol (m.p. l702C.).

Forty-five grams of the above prepared sulfonamide compound is dissolved in 100 ml. of 80% sulfuric acid and is left at room temperature for two hours. The solution is diluted with two volumes of water and extractedwith ether. The aqueous portion which contains 4'- chloro-2-(2-imidazolin-2-yl)benzophenone is neutralized with 50% sodium hydroxide solution while keeping the temperature below 25C. The solid is separated,

washed with water and recrystallized from dimethyl formamide to afford 23 g. of 5-(4-chlorophenyl)-2,3- v

dihydro-S H-irnidazol2,l-a]isoindol'5-ol which has the same analytical characteristics as the product of Example X. y

The above procedure is repeated to react a l,2,3,9b-

'tetrahydro-lH-imidazo[2,l-a]isoindol-5-one of Vlll- -XI1 with an appropriate sulfonyl halide, in pyridine, at a temperature within the range of about 80C. to above l 159C. for a period of about 2 to about 10 hours to afford the corresponding sulfonamide which is treated with about 80 to about 100 percent sulfuric acid to yield an appropriate 2-( 2-imidazolin-2- yl)benzophenone sulfate which is neutralized to produce a 2,3-dihydro-5l-1-imidazo[2,1-a] isoindol-S-ol.

EXAMPLE XVI EXAMPLE XVII Ten grams of 5-(4-chlorophenyl)-2,3-dihydro-5H- imidazo[2,1-a]isoindol-5-ol, as described in Example X, are suspended in ml. of absolute ethanol and then saturated with a continuous flow of hydrochloric acid gas. The resulting solution is filtered, evaporated to dryness and the residue recrystallized from ethanolethyl acetate to afford 4-chloro-2-(2-imidazolin-2- yl)benzophenone hydrochloride, m.p. 1702'C., dcc.. as a white crystalline solid which is soluble in water.

Analysis: Ultra Violet Absorption ETOH) infl. 223 p. (e= 19,100), max. 252 ,u (6 12,100), max. 265 ,u. (e 12,300); Infra Red Absorption (KBr) 1647 cm", 2,3003,200 cm.

Calcd for CmHmNgOCLHClI C, 59,80; H, 4.40; N, 8.72; Cl, 22.08. Found: C, 59.63; 114.50; N, 8.72; Cl,

Similarly, the following hydrochlorides are prepared:

2-(2-imidazolin-2-yl)-3',4diiodobenzophenone hydrochloride; 2'-(2-imidazolin-2-yl)-2-methyl-4',5-dipropoxypropiophenone hydrochloride; 3',4-diethoxy-2-(Z-imidazolin-Z-yl)benzophenone hydrochloride;

2-(2-imidazolin-2-yl)-4-methylbenzophenone hy' drochloride;

4'-hexyl-2-(2-imidazolin-2-yl)benzophenone hydrochloride;

4-amino-2-(2-imidazolin-2-yl)benzaldehyde dihydrochloride;

' I 3,4-dichloro-2-(2-imidazolin 2-yl)benzophenone hydrochloride; 4'-fluoro-2-(2-imidazolin 2-yl)benzophenone hydrochloride; and 3'-bromo-2-(2-imidazolin-2-yl)-4- methylbenzophenone hydrochloride.

EXAMPLE xvui When the procedure of Examples X XV are repeated with appropriate starting material, the following dihydroimidazoisoindolols are preparedwhich by the procedure described in Examples XVI XVII are then converted to their corresponding imidazolinyl phenyl carbonyl hydrochlorides.

DIHYDROIMIDAZOISOINDOLOLS lMlDAZOLlNYL PHENYL CARBONYL HYDROCHLORIDE 7-bromo-2,3-dihydro-5-(4-tolyl) SH-imidazol 2, 1 -a]isoindol-5-o1 2.3-dihydro-8-methyl-5-propyl- 5H-imidazol2,1-a]isoindol-5 ol 2,3-dihydro-9-iodo-5H-imidazo [2, 1 -a]isoindol-5-ol Similarly,

2,3-dihydro--( Z-phenethyl )-5 H- imidazo[2,l-alisoindol-S-ol is obtained by the oxida tion of l-phenethyl'l ,2,3,4,5,6-hexahydro-2,5-

benzodiazocine dihydrobromide with potassium dichromate.

EXAMPLE XXI Repeating the procedure of Example XX to oxidize a hereinafter listed hcxahydrobenzodiazocine, the following dihydroimidazoisoindolol compounds are prepared:

24 In the same manner, 1,2,3,4,5,6-hexahydro-l-(2,4- dimethoxyphenyl)-2,5-benzodiazocine is converted to 2,3-dihydro-5-(2,4-dimethoxyphenyl)-5H- imidazo[2,l -a}isoindol-5-ol.

EXAMPLE XXIV When the oxidation procedures of the previous Examples are repeated at temperature ranges from C. to 60C. for periods of up to about four hours on the HEXAHY DROBENZODIAZOCINE DIHYDROIMIDAZOISOINDOLOLS l.2.3.4.5.6 hexahydro-l-(pbromophenyl)-2.5 benzodiazocine dihydrochloride l.2,3.4.5,6-hexahydro-l-(pmethoxyphenyl)-2,5-benzodiazocine dihydrochoride l-benzyl-l,2,3,4,5.6-hexahydro-2.S-benzodiazocine dihydrobromide 1,2.3.4,5,6-hexahydro-l-(2- thienyl)2.5-benzodiazocine dihydrochloride l-(3-furyl)-l 2.3.4.5.6- hexahydro-2,5-benzodiazocine dihydrochloride l.2 3.4,5.6-hexahydro-8- methyl-l-phenyl-2.5benzodiazocine dihydrochloride l,2,3.4,5,6-hexahydro-l- (Z-pyridyl)-2,5 benzodiazocine dihydrochloride l.2.3.4,5,6-hexahydro-8.9 dimethoxy-l-(p -tolyl)-2;5- benzodiazocine dihydrochloride 5-(4-bromophenyl-2,3-dihydro- SI-Limidazol 2, l-alisoindol- 5-01 I 2,3 dihydro-5-(4-methoxyphenyl-SH-imidazolZ, I -a] isoindol-S-ol 5-benzyl-2.3-dihydro-5H- imidazolZ, l-alisoindol-S-ol 2.3'dihydro-7-methyl-5-phenyl -5Himidazo[ 2. l -a]isoindol- 5 ol EXAMPLE XXII following hexahydrobenzodiazocines the hereinafter listed dihydroimidazoisoindolol compounds are ob- EXAMPLE XXIII One gram of l,2,3,4,5,6-hexahydro-l-phenyl-2,5- benzodiazocine dihydrochloride is dissolved in 25 ml. of water. A solution of 0.5 g. of potassium permanganate in 25 ml. of water is added over a period of one hour. The mixture is filtered to remove precipitated inorganic salts and the filtrate is made alkaline with a potassium bicarbonate solution. The precipitated product is separated and recrystallized from ethanol. The prod-. 60

uct obtained in this manner is 2,3-dihydro-5-phenyl- 5H-imidazo[2,l-a]isoindol 5-ol which has thesame physical characteristics as the identical compoundof Example XII.

tained:

HEXAHYDROBENZODIAZO- C INES DIHYDROIMIDAZOISOIN- DOLOLS 1.2.3.4.5 .o-hexahydrol 5,6- 7,8-tetrahydro-2-naphthyl)- 2,5-benzodiazocine l,2,3,4.5.6-hexahydro-l-(ptrifluoromethylphenyl )-2,5- benzodiazocine 1.23.4.5 .6-hexahydro-8,9- dichloro-l-phenyl-2,5- benzodiazocine l-(p-ethylphenyl-1,2,35,4- 5.6-hexahydro-2,5benzodiazocine .8,9-dibromo-l 2,3,45,6- hexahydrol -phenyl-2,5- benzodiazocine l,2.3,4.5.6-hexahydro-9- methylaminol p-tolyl 2.5-benzodiazocine 2.3-dihydro-5-(5,6,7,8- tetrahydro-Z-naphthyl)-5I-limidazo[ 2 l -a]isoindol-5-ol 5-(4-trifluoromethylphenyl 2,3-dihydro-5H-imidazo [2. l -a]isoindol.-5-ol 7,8-dichloro-2,3-dihydro- 5-phenyl-5H-imidazo[ 2. l -a] isoindol-S-ol 5-(4-ethylphenyl-2.3-dihydro-5H-imidazo[ 2. I -a isoindol-5-ol I 7,8-dibromo-2,3-dihydro- S-phenyl-SH-imidazolZ. l -a] isoindol-S-ol 2.3-dihyd ro-8-methylamino- 5-( 4-tolyl )-5H-imidazo [2, l -a]isoindol-5-ol EXAMPLE XXV Ten grams of l-( 3,4-dichlorophenyl)-l ,2,3,4,5,6- hexahydro-Z,S-benzodiazocine dihydrochloride are dissolved in 250 ml. of water. A solution of5.0 g. of potassium permanganate in 250 ml. of water is added over EXAMPLE XXVI When the oxidation procedure of Examples XX to XXV is repeated employing the following hexahydrobenzodiazocines as starting materials, the hereinafter listed dihydroimidazoisoindolol compounds are produced.

HEXAHYDROBENZODIAZO- DlHYDROlMIDAZOlSOlN CINES DOLOLS l-( p-ethoxyphenyl 1 2,3,4, 5(4-ethoxyphenyl )-2,3 5.6-hexahyd ro-2,5-benzodiazodihydo-5H-imida2o[ Z. l -a] cine isoindol-S-ol 8-ethyl-l t2,3,4,5,6-hexahydro l -phenyl-2 .S-benzodiazocine l,2,3.4.5.6hexahydro-8,9- dimethyl-l-phenethyl-2.5- benzodiazocine S-fluorol ,2 ,3,4,5,6-hexahydrol -(p-tolyl )-2,5- benzodiazocine What is claimed is:

1. A process for the preparation of a compound having the formula:

R2 191 1.... it

wherein R is selected from the group consisting of lower alkyl, phenyl, lowcr alkylphenyl, lower alkoxyphenyl, di(lower) alkylphcnyl. di(lower)alkoxyphenyl, aminophenyl, trifluoromethylphenyl,

5 monohalophenyl, dihalophenyl, furyl, thienyl and naphthyl; R is selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy; R is hydrogen when R and R are dissimilar and when R and R are the same they are both selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy which comprises contacting a benzodiazocine of the formula:

wherein R R and R are defined as above, with an oxidizing agent in a reaction-inert solvent at a tempera 30 ture from about 20C. to about 60C. for a period of about khour to about 4 hours.

2. A process as described in claim 1 wherein the oxidizing agent is selected from the group consisting of potassium permanganate, potassium dichromate and potassium chlorate.

3. A process as described in claim 1 wherein the oxidizing agent is selected from the group consisting of potassium permanganate, potassium dichromate and potassium chlorate; the reaction-inert solvent is water; and the reaction is conducted at about room temperature.

4. A process as described in claim 1 wherein the oxidizing agent is potassium permanganate; the reactioninert solvent in water; and the reaction is conducted at about room temperature.

* =l= =l l= 

1. A PROCESS FOR THE PREPARATION OF A COMPOUND HAVING THE FORMULA:
 2. A process as described in claim 1 wherein the oxidizing agent is selected from the group consisting of potassium permanganate, potassium dichromate and potassium chlorate.
 3. A process as described in claim 1 wherein the oxidizing agent is selected from the group consisting of potassium permanganate, potassium dichromate and potassium chlorate; the reaction-inert solvent is water; and the reaction is conducted at about room temperature.
 4. A process as described in claim 1 wherein the oxidizing agent is potassium permanganate; the reaction-inert solvent in water; and the reaction is conducted at about room temperature. 